Ubiquitin positive inclusions are found in amyotrophic lateral sclerosis (ALS), a prototypic motor neuron disease and frontotemporal lobar degeneration (FTLD), the second most common dementia after Alzheimer's disease in patients <65. Recently, investigators at the University of Pennsylvania (PENN) identified TDP-43 as the disease protein ubiquitinated in both disorders. Since motor neuron disease and dementia are found in ALS and FTLD, and since the same disease protein accumulates in both disease entities, this suggests that ALS and FTLD represent the same clinicopathological spectrum of a neurodegenerative syndrome. Thus, the major goals of this Program Project Grant (PPG) is to develop a vigorous research program focused on elucidating the etiology and pathogenesis of TDP-43 proteinopathies in ALS without or with cognitive impairment or dementia (designated as ALS, ALS-Cog and ALS-FTLD, respectively) and compare them to FTLD with and without ALS. The investigators of this new PPG are a close-knit and highly integrated multidisciplinary group of PENN physicians and basic scientists who have formed a productive collaborative alliance and established a very comprehensive clinical and basic science research program at PENN to study ALS, ALS-Cog and ALS-FTLD in patients, in human postmortem tissues and in model systems. These investigators propose a set of bold objectives for ALS and FTLD research that will be implemented through 4 Cores and 3 Projects. Specifically, they will: 1) recruit ALS, ALS-Cog and ALS-FTLD patients; 2) develop new algorithms to characterize the cognitive impairments and dementia in ALS patients; 3) test the hypothesis that there is a tight link between language and motor systems in the representation of action verbs; 4) further characterize the spectrum of TDP-43 neuropathologies in ALS, ALS-Cog and ALS-FTLD brains and compare them with FTLD with and without ALS; 5) identify hyperphosphorylated residues and N-terminal cleavage sites that generate C-terminal fragments in pathological TDP-43 and determine their significance in mechanisms of TDP-43 proteinopathies; 6) establish cell culture and transgenic mouse models of TDP-43; 7) use these models to elucidate the pathogenic mechanisms of neurodegeneration in TDP-43; 8) determine if genetic variants in TDP-43 found in patients with ALS, ALS-Cog and ALS-FTLD are disease risk factors or pathogenic disease causing mutations; These and other studies will lead to improved understanding of the cognitive impairments and dementia in ALS as well as provide insights on the diagnosis and treatment of these disorders.